Ergoline

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

The ergolines have provided a number of drugs that show interaction with neurotransmitters. Depending on the substitution pattern, they may be dopamine agonists or antagonists, a-adrenergic blockers, or Inhibitors of the release of prolactin. A recent member of the series, pergolide... 

The technical aspect of 2-bromo-a-ergocryptine synthesis, including the characterisation and significance of the impurities obtained in the production process, were reviewed. In the continuation new ergolene and ergoline compounds were synthesized and tested for the pharmacological activity. 

In general, the introduction of bromine in ergolene or ergoline structure results in remarkable change in pharmacological activity of the parent compounds. After intensive research work of several research groups many useful methods for 2-bromination have been developed. Practically, all methods are accompanied with many side reactions. Therefore, the best attainable yields of product 2 are in the range of 60 - 70 % of the theory ... 

Surprisingly, the bromination of ergoline structures with N-bromosaccharin yielded as the main product the ergoline derivatives with a saccharin on the position 2 instead of the expected 2-bromo-derivatives ... 

A series of corresponding ergoline and ergolene derivatives was synthesized. The ergotamine derivative showed an interesting antihypertensive activity. Unfortunately, the substance has very poor solubility and stability and therefore the further pharmacological evaluation was stopped (ref. 25). 

P)-/V-[3-(Dimethylamino)propyl]-lV-[(ethylamino)carbonyl]-6-(2-propenyl)ergoline-8-carboxainide... 

Ergocomine lb 243 Ergocristine lb 245,348 Ergocryptine lb 379 Ergoline carboxylic acids lb 243 Ergometrine lb 243,252,440,444 Ergosterol la 351... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

For fenfluramine, MDMA and methysergide, in vivo oxidation gives rise to a more potent 5-HT2B receptor agonist than the parent compound. The oxidized nitrogen is indicated by a solid arrow. Note that all drugs fall into one of the two structural classes phenylisopropylamines (top) and ergolines (bottom). 

Die Clavin-Alkaloide kommen besonders in Sklerotien verschiedener Claviceps-S cvts vor, die auf femostlichcn und afrikanischen Grasem parasitieren. Saprophytische Kulturen dieser Pilze bilden ebenfalls diese einfachen Ergolin-Dcrivatc. In Spuren sind sie auch in Sklerotien und saprophytischen Kulturen von Claviceps purpurea nachgewiesen worden. 

---